Coronary artery disease remains the leading cause of mortality in the western world. Chronic total occlusions (CTO), defined as occlusions of more than a month old, are very common in patients undergoing diagnostic coronary artery catheterization with up to 20% of patients reported to have one or more CTO (1). This includes a large number of patients that have not actually had a myocardial infarction. Successful revascularization of CTO significantly improves angina in symptomatic patients (2, 3) and more recent data demonstrate improvement in left ventricular function (4-7), and even in reduction of mortality (8-10). Currently there are two possible therapeutic strategies for CTO revascularization: coronary artery bypass graft surgery (CABG) or percutaneous coronary interventions (PCI) (angioplasty or stenting). Successful angioplasty requires that the operator place a small (360 μm diameter) guide-wire through the tissue obstructing the lumen in a CTO in order to reach the distal arterial lumen. The technical difficulty of performing PCI in CTO, primarily because of inability to cross CTO with a guide wire, is reflected in the low rates of PCI for CTO (accounts for <8% of all PCI), despite the benefits of a positive outcome (11). Since PCI have severe limitations in this patient subset, clinicians frequently decide to refer these patients for CABG or persist with (often ineffective) medical therapy. The presence of one or more CTO of vessels supplying viable myocardium remains one of the most common reasons for referral for CABG rather than attempting PCI (12).
The definition of a CTO is based on an angiographic appearance of complete absence of contrast reagent in a segment of an epicardial coronary artery. The distal artery beyond the CTO may not be visible or may be perfused by anterograde collaterals that are outside of the vessel lumen (termed “bridging collaterals”) or by retrograde collaterals that originate from adjacent coronary vessels. Procedural success rates in stenotic (but non-occluded) coronary artery lesions are in excess of 95%. However, procedural success rates for CTO are only in the 60 to 70% range (3, 13, 14), with only modest improvement over the 50-60% success rates in the 1980's (23, 24), despite some improvements in angioplasty technology (25, 26). This current success rate for CTO is probably an overestimation in the sense that the majority of CTO are probably never even attempted due to expected failure.
Inability to cross the CTO with a guide-wire is responsible for upwards of 75% of PCI failures (14, 15). In a minority of cases, the balloon or stent cannot cross the lesion despite successful guide-wire crossing. Despite its common occurrence, there is surprisingly little information about the pathophysiology of CTO, and why some CTO can be crossed while others are unsuccessful.
The initial acute event leading to the development of a CTO is a ruptured atherosclerotic plaque with bidirectional thrombus formation. The thrombus and lipid-rich cholesterol esters are gradually replaced over time by the formation of collagen and calcium deposits (16, 17). This fibrous tissue is particularly dense at the proximal and distal ends of the lesion, which typically are the most resistant areas of the CTO for guide-wire crossing. Proteoglycans are also important components of the CTO within the first year (16). In later stages, the lesion becomes more calcified (16, 17). Despite the angiographic appearance of a CTO, microvessels are quite common in CTO (>75%), regardless of occlusion duration (FIG. 1) (16).
There are three types of microvessel formation in arteries with advanced atherosclerotic lesions. The first pattern occurs in the vasa vasorum, which are the fine network of microvessels in the adventitia and outer media. These vessels proliferate in atherosclerosis and in response to vascular injury such as angioplasty and stenting (18-20). Hypoxia in the outer levels of the vessel wall appears to act as an important stimulus (36). Occasionally in CTO, these adventitial blood vessels are well developed and can be recognized as “bridging collaterals”. Second, neovascularization can develop within occlusive intimal plaques, predominantly in response to chronic inflammation (21). Plaque neovascularization has been associated with progression of experimental atheromas in various animal models (22-25). The localization of plaque vessels in so-called “hot spots” in the shoulders of atheromas may predispose these plaques to rupture and acute coronary events (26, 27). The third type is the pattern of microvessel formation (known as “recanalization”) that occurs as part of the organization phase in CTO in which thrombus is replaced by fibrous tissue. These microvessels generally range in size from 100-200 μm but can be as large as 500 μm (21). In contrast to the vasa vasorum which run in radial directions, these intimal microvessels run within and parallel to the thrombosed parent vessel (28).
Knowledge of thrombus organization comes largely from the study of veins. This process resembles the pattern of wound healing (29). Initially, the freshly-formed thrombus contains platelets and erythrocytes within a fibrin mesh, which is followed by invasion of acute inflammatory cells (44). Neutrophils predominate at first but are later replaced with mononuclear cells. (30, 31). Endothelial cells also invade the fibrin lattice and form tube-like structures and microvessels within the organizing thrombi (29, 32).
Relatively little is known about the process of microvessel formation in arterial thrombi. It cannot be assumed that the processes are identical in veins and arteries. Arterial thrombi recanalize less frequently and to a lesser extent than venous thrombi (33). The behavior of venous cells can differ substantially from their arterial counterparts (34, 35). Microvessels have been reported in 2-week-old mural thrombi in porcine aortas, which were attributed to mononuclear blood cells originating within the thrombus, with no apparent contribution from cells native to the vessel wall (36) or from invasion of vasa vasorum from the vessel wall (37, 387). Inflammation may also play a role since high concentrations of macrophages have been detected in regions of recanalization in spontaneous human thrombi and in experimental animal arterial thrombi (31, 39). The local ECM environment is probably an additional important modifier, with specific matrix components exerting either a pro-angiogenic (hyaluronan (40, 41), fibronectin (42, 43), perlecan (44-46), versican (47)), or anti-angiogenic (type I collagen (40, 48) decorin (49, 50)) effects.
We have observed the presence of a variable number of microvessels in CTO. These preliminary observations suggest the possibility that these microvessels assist in successful CTO guide-wire crossings (see below). Microvessels have also been observed in a limited number of human coronary CTO studies (16), which has led us to the concept that intraluminal vascularization, and its effects on structural and mechanical properties of lesion, may substantially facilitate CTO guide-wire crossing rates. This can be studied using imaging techniques including magnetic resonance imaging (MRI) and 3D micro computed tomography (micro CT).